Ethnobotany: Chemistry and Medicinal Properties of Plants (2nd Lecture)

Paclitaxel

Pacific Yew (Taxus brevifolia)

Plants, People and Culture: The Science of Ethnobotany; Michael Balick and Paul Alan Cox

Coca Plant vs Cacao or Cocoa Plant

Erythroxylum coca—

Source of cocaine and grown in

South America (Peru,Columbia,

Argentina, Bolivia

Yes coca extract was used in Coca-

Cola until early 1900’s

Theobroma cacoa

Source of chocolate or cocoa

Grown in Central Africa (Ivory Coast and

Ghana) and Central America and South

America

Alkaloids

Alkaloids: natural products that contain a basic nitrogen

Isolated from club mossInhibits acetylcholinesterase and is

N-Methyl-D-aspartate receptor antagonist (NMDA receptor)

Treatment of Alzheimer’s Disease-improves cognition

Antileukemia: isolated from Madagascar Periwinkle (Catharanthus roseus)Tropical plant

Alkaloids

Morphine

Caffeine

Cocaine

Inhibits reuptake of neurotransmittors(serotonin-norepinephrine-dopamine) at synapseLocal Anesthetic --- used in dentistry at one time

Analgesic and works by binding to μ-opioidreceptors is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression.

Acts as a stimulant and found in coffee, tea, kola nutsAntagonist at the adenosine receptor which is a receptor that slows down neural activity

Ephedrine and Pseudoepedrine

Isolated from Epedra sinicaBronchodilator: treatment of asthma where bronchioles are

constricted limiting oxygen exchange in lungsSide effects: tachycardia(increase heart rate) vasoconstriction(constricts blood vessels) and increase blood pressure, appetite suppressant

Ephedrine and Pseudoepedrine

Ephedrine and Pseudoephedrine are tightly controlled today because it is easy to convert into methamphetamine

Methamphetamine

What are Bath salts and what is the pharmacology???

Methenedioxypyrovalerone (MDPV) Methamphetamine

Methamphetamine opens DopamineTransporter and allows DA to move in-out of dopaminergic nerve terminal and doesSame at the Vesicular monoamine transporter that is within the nerve terminal

DAT= dopamine transporterVMAT= vesicular monamine transporter

Phenols and Carboxylic Acids

Hydroxyl Group

Aromatic Ring

Carboxylic Acid Group

Aromatic Ring

Salicylic Acid: comprised of three components: 1) Phenol 2) carboxylic acid 3) aromatic ring

Salicylic Acid and Derivatives

Salicylic Acid found on the inner bark of

willow tree

Many roles in willow trees:

1) phytohormone—plant growth

2) ion uptake

3) transpiration—movement of H2O and

nutrients in a plant

4) endogenous signaling—defense against

pathogens by producing proteins to protect

against infection

Salicylic Acid and Derivatives

Aspirin or 2-Acetylsalicylic Acid

IUPAC Name or Chemical nameTrade Name

Background:

40,000 tons/yr aspirin consumed worldwide (~80,000,000 lbs or 1000 semi loads)

Belongs to family of drugs: Non-steroidal Anti-inflammatory Drugs (NSAID)

Used to treat: fever (antipyretic); anti-inflammatory; anti-thrombotic ( prevents strokes

and heart attack) and analgesic

Some evidence that aspirin prevents tumorigenesis ( initiation and growth of tumors)

Aspirin inhibits enzymeCOX-1 and COX-2

How Aspirin Works

COX-1: promotes the production of the natural mucus lining to protectthe inner stomach and contribute to reduced acid secretion

COX-1: Platelets contain COX-1 which use Thromboxane (TXA2) in clotting

Induces fever

Inflammation

Nitrogen Cycle: Oxidized and Reduced Forms of Nitrogen

The nitrogen cycle is the process by which nitrogen is converted between its various chemical forms i.e. oxidized and reducedAtmosphere: ~78% N2 but limited availability for biological use

N2 must be “fixed” to be usable by plants either in the form of NH4+ or NO3

-or NO2

-

Most fixation is done by free-living or symbiotic bacteria using a nitrogenase enzymethat combines gaseous nitrogen with hydrogen to produce ammonia.

Nitrogen FixationNitrogen fixation is the natural process, either biological or abiotic(non-biological) by which nitrogen (N2) in the atmosphere is converted into ammonia (NH3).

Fixed nitrogen is required to biosynthesize the basic building blocks of life, e.g., nucleotides for DNA and RNA and amino acids for proteins.

Plants that contribute to nitrogen fixation include the legume family, Fabaceae, which includes clovers, soybeans, alfalfa, lupines, peanuts

Nitrogen also used to make alkaloids (nitrogen containing phytochemicals)

Why Plants Need Nitrogen in the NH3 or Reduced Form

All of the nitrogen containing compounds that plants require a reduced

nitrogen

Nitrogen Containing Chemistry: amino acids and nucleic acids for DNA

and RNA nucleosides in DNA

R CH C

NH2

OH

O

Amino

Acid (carboxylic acid)

Proteins

Biopolymers of -amino acids.

Amino acids are joined by peptide bond.

Function of proteins:

Enzymes-to catalyze chemical reactions

Transport—move nutrients

Protection-defense against infections (antibodies)

Hormones-needed for growth

The Protein Structure

The amino acids are joined by amide linkages called peptide bonds.The global physical and chemical properties of a protein are determined

by its constituent amino acids.

Human Hormone Bradykinin

The human hormone bradykinin is a nonapeptide-nine Amino AcidsFree -NH3+ at its N terminus and a free -COO- at its C terminusA peptide is any polymer of amino acids linked by amide bonds between

NH2 group of one amino acid and the CO2H of the neighboring amino acid.

Bradykinin: dilates blood vessels and reduces blood pressure

Nucleic Acids

N

NN

N

NH2

O

HOH

H

HO

Adenine

2-D-deoxyribose

N

NN

N

NH2

O

OHOH

HO

2-D-ribose

Adenine

Deoxyribonucleic AcidsRibonucleic Acids

Common Deoxyribonucleosides (DNA)

Four common deoxyribonucleosides that make up DNA

The structure of the DNA polymer is similar to that of RNA, except there

are no hydroxyl groups on the 2' carbon atoms of the ribose rings.

Ribonucleosides (RNA)

A -D-ribofuranoside bonded to a heterocyclic base at the anomericcarbon.

Ribonucleosides = base + sugar (ribofuranoside)

Phytosterols (Plant Steroids)

Sterols Stanols

Contain 4-rings joined together, often will be three-six carbon rings (hexane or hexene)

rings and one is a 5-membered ring (pentane)

Shown to reduce blood cholesterol levels in humans by competing with cholesterol

for absorption from intestines (not as effective as statin drugs)

Brassinosteroids: Plant Growth Hormone

Ester

Esters in one of the 4-rings of steroids is very unusual

Promotes cell elongation and expansion with

auxin (another plant hormone)

Cardiac glycosides

SteroidGlycoside : A carbohydrate or sugar attached to none

carbohydrate piece of the molecule which happens to be a

steroid in this case

Digoxin or digitalis : isolated from foxglove plant

Used to treat atrial fibrillation which is a cardiac arrhythmia

Carbohydrates: organic molecules that contain carbon,

hydrogen and oxygen

Saccharides or Carbohydrates

1)Composed of only the elements of carbon, hydrogen

and oxygen

2) The terms saccharide, carbohydrate and sugar are

used synonymously

3)Glycoside: attach a sugar, or carbohydrate to a non-

carbohydrate

Classification of Carbohydrates

A carbohydrate can be classified as:

1.Monosaccharide: simplest

2.Disaccharide: 2-monosaccharides

3.Oligosaccharide: 3-6 monosacch.

4.Polysaccharide: many, many monsaccharides linked

Salicin:

Glycoside Attached

Plants will store molecules by

making a glycoside which makes the

structure more water soluble.

Source is willow tree bark

Metabolized in-vivo (in your body)

to the anti-inflammatory compound

salicylic acid

Plants do the same to form salicylic

acid which is a plant growth hormone

Metabolized to Salicylic Acid

Salicylic Acid

Willow tree use salicylic acid as a growth hormone, plant

defense to signal production of proteins to fight infection,

ion uptake and transpiration

Salicylic acid: antipyretic, anti-inflammatory, and

analgestic in mammels

Cardiac glycosides

SteroidGlycoside : A carbohydrate or sugar attached to none

carbohydrate piece of the molecule which happens to be a

steroid in this case

Digoxin or digitalis : isolated from foxglove plant

Used to treat atrial fibrillation which is a cardiac arrhythmia

Carbohydrates: organic molecules that contain carbon,

hydrogen and oxygen

Glycoside: Steroid and

a Carbohydrate or sugar

Source of testosterone if remove the sugar

Sugar Steroid

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Cellulose• Cellulose is the most abundant organic substance

found in nature.

• It is the chief structural component of plants and found in cell walls of plants

• Cotton fibers ~100% cellulose

• -1,4-glycosidic linkage

• Humans cannot hydrolyze the -1,4-glycosidic linkage nor is there an enzyme present in the body to break the bond. Herbivores and termites have microbes present in the gut or rumen that can break the -1,4-linkage

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Representation of cellulose.

Glucose

Nucleic Acids are Glycosides

N

NN

N

NH2

O

HOH

H

HO

Adenine

2-D-deoxyribose

N

NN

N

NH2

O

OHOH

HO

2-D-ribose

Adenine

Deoxyribonucleic AcidsRibonucleic Acids

Carbohydrate is attached to a base in both DNA and RNA

Echinacea: Phytotherapy Research

Phytotherapy Research 2005 Aug 19(8) 689-94A Proprietary Extract from the Echinacea Plant (Echinacea purpurea) enhances Systemic Immune Response During a Common Cold

Goel, V; Lovlin, R; Chang,C; Slama, JV; Barton, R et.al.

Echinilin (Factors R and D Technologies)from Echinacea purpureaand is standardized based on three active components is reported to be effectivefor the treatment of the common cold.

Admin for 7 days after symptoms of cold with 8-doses in day one3-doses each subsequent day Increased no. of total white blood cells, monocytes, neutrophils

and natural killer (NK) cells in treated patients vs placebo Reduced production of superoxide in neutrophils in later stages of infection(??)Conclusion: enhances non-specific immune response MAY lead to faster resolution of

cold symptoms

Echinacea (Echinacea purpurea)

Nine species of Echinacea are known

Three have been studied for medicinalproperties: Echinacea purpurea, angustifolia,and pallida

Interest in the immunological effects as immunostimulator or an

immunomodulator??Some believe: cuts chances of catching a cold and shortens

the duration of cold---no solid evidence to support2003: Double blind study: no effect on rates of infection or duration norintensity neither tester nor subject know content of pill

1) Critics: not high enough dose and did not contain the3-components found in echinacea that are reported to bethe active ingredients

Echinacea: Active Compounds

Three classes of compounds are reported to be present in Echinacea

1) Polysaccarides—sugars??2) Alkylamides—see below3) Phenols—cichoric acid

Alkylamides

Echinacea: Alkylamides

Alkylamides from Echinacea Are a New Class of Cannabinomimetics(J. of Biological Chemistry 2006, 14192-14206)

Two cannabinoid receptors:1) CB1—nervous system-THC2) CB2– immune cells (i.e. neutrophils,NK cells)

Results: affect inflammation more than the immune response

Echinacea: Cichoric Acid

Stimulates Phagocytosis in Immune Cells i.e. Neutrophils1) Oxygen-dependent degradation involving “Reactive

Oxygen Species” (ROS)

2) Oxygen-independent degradation involving proteolytic enzymes and lactoferrin (iron sequestering enzyme)

Neutrophils and Red Blood Cells

Neutrophils contain three enzymes: NADPH Oxidase (Nicotinamide Adenine DinucleotideOxidase), Superoxide Dismutase and Myeloperoxidase that will generate bleach.

Superoxide Dismutase

NADH Oxidase

Myeloperoxidase

Formation of Radicals in Biological Systems (i.e. Cytochrome P450)

Generate Hydroxide Radical

.OH

Radical Inhibitors• Often added to food to retard spoilage.

• Without an inhibitor, each initiation step will cause a chain reaction so that many molecules will react.

• An inhibitor combines with the free radical which was formed in the initiation step to form a stable molecule.

• Vitamin E and vitamin C are thought to protect living cells from reactive, high energy free radicals.

• Mechanistically they are almost acting as a “Terminator of a Chain Reaction” yet radical is still present with Vitamin C or hydroxyanisole, but not as reactive because of delocalization of the radical.

Radical Inhibitors

Vitamin C radical is resonance stabilized therefore not able to react further with radicals

OO

HOH

OHH

OHO

H

+ RO

OO

HOH

OHH

OHO

+ RO

H

OO

HOH

OHH

OHO

OO

HOH

OHH

OHO

O

O

H

Vitamin E (α-tocopherol)

O

H

BHT (Butylated hydroxytoluene)

Other Antioxidants

Antioxidants in Dark Chocolate: Form Stabilized Radicals